The proposed studies are designed to investigate the physiological importance and consequences of a newly described feedback regulatory system that controls acid-base homeostasis by regulating endogenous acid production. Studies will be performed in man and rats in situations where endogenous acid production is increased. The effect of acidosis (NH4Cl and methionine) and alkalosis (NaNCO3) on lactic acid production in the forearm under anerobic conditions will be tested in normal volunteers, subjects on hypocaloric ketogenic diets and patients with renal failure, to investigate whether exogenous or endogenous acid loads or retained acid can influence further endogenous acid production. The effect of acid and base loads on ketoacid production in subjects on hypocaloric ketogenic diets will be examined to evaluate the consequences of altered fat (ketone) metabolism on protein conservation and fuel utilization. This will be accomplished by measuring nitrogen balance and thermogenesis during acid-base inhibition and stimulation on ketogenesis. In chronically catheterized rats made ketotic with a Crisco diet, we will investigate the time course and reversibility of acute metabolic acidosis (HCl infusion), alkalosis (NaHCO3 infusion), chronic metabolic acidosis (CaCl2 in diet), alkalosis (chloride depleted high base diet) and acute respiratory acidosis and alkalosis on ketoacid production. As endogenous acid generation usually occurs in settings of specific energy need, eg. lactic acid during exercise and ketoacids during starvation, a regulatory mechanism independent of those needs may have widespread implications for energy utilization in physiological or pathological situations.